Pre-synaptic kainate receptor-mediated facilitation of glutamate release involves PKA and Ca2+-calmodulin at thalamocortical synapses
Article first published online: 11 JUN 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 126, Issue 5, pages 565–578, September 2013
How to Cite
J. Neurochem. (2013) 126, 565–578.
- Issue published online: 23 AUG 2013
- Article first published online: 11 JUN 2013
- Accepted manuscript online: 20 MAY 2013 11:35AM EST
- Manuscript Accepted: 17 MAY 2013
- Manuscript Revised: 24 APR 2013
- Manuscript Received: 7 DEC 2012
- Spanish Ministry of Education and Culture. Grant Number: BFU2006-1455/BFI
- Eugenio Rodríguez-Pascual Foundation
- calcium calmodulin;
- kainate receptors;
We have investigated the mechanisms underlying the facilitatory modulation mediated by kainate receptor (KAR) activation in the cortex, using isolated nerve terminals (synaptosomes) and slice preparations. In cortical nerve terminals, kainate (KA, 100 μM) produced an increase in 4-aminopyridine (4-AP)-evoked glutamate release. In thalamocortical slices, KA (1 μM) produced an increase in the amplitude of evoked excitatory post-synaptic currents (eEPSCs) at synapses established between thalamic axon terminals from the ventrobasal nucleus onto stellate neurons of L4 of the somatosensory cortex. In both, synaptosomes and slices, the effect of KA was antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted after pre-treatment with a cocktail of antagonists of other receptors whose activation could potentially have produced facilitation of release indirectly. Mechanistically, the observed effects of KA appear to be congruent in synaptosomal and slice preparations. Thus, the facilitation by KA of synaptosomal glutamate release and thalamocortical synaptic transmission were suppressed by the inhibition of protein kinase A and occluded by the stimulation of adenylyl cyclase. Dissecting this G-protein-independent regulation further in thalamocortical slices, the KAR-mediated facilitation of synaptic transmission was found to be sensitive to the block of Ca2+ permeant KARs by philanthotoxin. Intriguingly, the synaptic facilitation was abrogated by depletion of intracellular Ca2+ stores by thapsigargin, or inhibition of Ca2+-induced Ca2+-release by ryanodine. Thus, the KA-mediated modulation was contingent on both Ca2+ entry through Ca2+-permeable KARs and liberation of intracellular Ca2+ stores. Finally, sensitivity to W-7 indicated that the increased cytosolic [Ca2+] underpinning KAR-mediated regulation of synaptic transmission at thalamocortical synapses, requires downstream activation of calmodulin. We conclude that neocortical pre-synaptic KARs mediate the facilitation of glutamate release and synaptic transmission by a Ca2+-calmodulin dependent activation of an adenylyl cyclase/cAMP/protein kinase A signalling cascade, independent of G-protein involvement.
Ca2+/calmodulin involvement in pre-synaptic kainate receptors facilitation of glutamate release at thalamocortical synapses. We determined the mechanism by which kainate receptors (KARs) mediate a facilitation of glutamate release at thalamo-L4 cortical cell synapses. We find that an increase in cytosolic Ca2+ concentration, contingent on extra- and intra-cellular sources, in the pre-synaptic thalamic neuron, operates through the formation of Ca2+-calmodulin complexes to activate an AC/cAMP/PKA signalling pathway. This action of KARs may support learning and memory processes.